US5300511A - Spiro-benzopyran derivatives and useful for treating asthma and hypertension - Google Patents

Spiro-benzopyran derivatives and useful for treating asthma and hypertension Download PDF

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Publication number
US5300511A
US5300511A US07/887,189 US88718992A US5300511A US 5300511 A US5300511 A US 5300511A US 88718992 A US88718992 A US 88718992A US 5300511 A US5300511 A US 5300511A
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Prior art keywords
benzopyran
methyl
aromatic
oxopyridyl
mmole
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Inventor
Sung-eun Yoo
Kyu Y. Yi
Nak C. Jeong
Jee H. Suh
Seon-Ju Kim
Hwa-Sup Shin
Byung H. Lee
Kyu S. Jung
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Korea Research Institute of Chemical Technology KRICT
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Korea Research Institute of Chemical Technology KRICT
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Assigned to KOREA RESEARCH INSTITUTE OF CHEMICAL TECHNOLOGY A CORP. OF KOREA reassignment KOREA RESEARCH INSTITUTE OF CHEMICAL TECHNOLOGY A CORP. OF KOREA ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: YOO, SUNG-EUN, JEONG, NAK C., JUNG, KYU S., KIM, SEON-JU, LEE, BYUNG H., SHIN, HWA-SUP, SUH, JEE H., YI, KYU Y.
Priority to US08/164,392 priority Critical patent/US5493029A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to novel benzopyran derivatives which have excellent effectiveness in the treatment of hypertension by lowering blood pressure with a relaxation activity on vascular smooth muscle and, further, in the treatment of asthma by relaxing respiratory smooth muscle.
  • the present invention also relates to processes for preparing such compounds; and to pharmaceutical compositions containing such compounds as an active ingredient.
  • R a and R b is a hydrogen atom and the other is selected from the group consisting of a C 1-6 alkyl- and alkoxycarbonyl, C 1-6 alkyl-carbonyloxy, C 1-6 alkylhydroxymethyl, nitro, cyano, chloro, trifluoromethyl, C 1-6 alkyl- and alkoxysulfinyl, C 1-6 alkyl- and alkoxysulfonyl, C 1-6 alkyl- and alkoxycarbonylamino, C 1-6 alkyl- and alkoxysulfinylamino, C 1-6 alkyl- and alkoxysulfonylamino, C 1-6 alkyl- and alkoxythicarbonyl, C 1-6 alkyl- and alkoxythiocarbonyloxy, C 1-6 alkylthiomethyl, formyl, an optionally substituted aminosulfinyl, aminosulfonyl or aminocarbonyl, or a terminal substituted e
  • R a and R b is nitro, cyano or a C 1-6 alkylcarbonyl group and the other is methoxy or an optionally substituted amino group;
  • R c and R d are a hydrogen atom or a C 1-4 alkyl, and the other is a C 1-4 alkyl group; or
  • R c and R d together form a C 2-5 polymethylene
  • X' is an oxygen or sulfur atom
  • Y' and Z' are hydrogen atoms or together form a single bond; and n is 1 or 2.
  • European Patent Publication No. 298,452 A2 filed by F. Hoffmann La Roche & Co. discloses benzopyran derivatives of formula(B) and pharmaceutical compositions containing same: ##STR5## wherein: R e is a hydrogen or halogen atom, or a trifluoromethyl, nitro, cyano, a lower alkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkanoyl, carbamoyl or mono- or di(lower alkyl) carbamoyl group;
  • R f is a hydrogen atom, lower alkyl or phenyl group
  • R g is a hydrogen atom or lower alkyl group
  • R h is a hydrogen atom or a hydroxy group; and, R i is a hydrogen atom; or R h and R i together form a C--C bond; and
  • R j is an aryl- or N-heteroaryl group whose 2-position is a hydroxy group, or, an N-oxide group in case of N-heteroaryl group.
  • Korean Patent Application No. 91-4602 filed by Merck Patent Gesellshaft mit be excter legislation discloses a chromane derivative of formula(C) and a salt thereof: ##STR6## wherein R k is H or A;
  • R 1 is F, Cl, Br, I, OH, OA, OAc, SA, NO 2 , NH 2 , NHA, NA 2 , CH or COOA;
  • R m is H, OH, OA or OAc and R n is H; or R m and R n together form a single bond;
  • R O is an optionally mono- or di-substituted pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxohydropyridyl, oxodihydropyridyl, oxodihydropyridazinyl, oxodihydropyrimidinyl, oxodihydropyrazinyl, 2-pyrrolidinon-1-yl or 3-oxocyclopenten-1-yl with A, F, Cl, Br, I, OH, OA, OAc, SH, NO 2 , NH 2 , NHAc, COOH and/or COOA;
  • R p and R q are each independently H, A, HO, AO, CHO, ACO, ACS, HOOC, AOOC, AO--CS, ACOO, A--CS--O, hydroxyalkyl, mercaptoalkyl, NO 2 , NH 2 , NHA, NA 2 , CN, F, Cl, Br, I, CF 3 , ASO, ASO 2 , AO--SO, AO--SO 2 , ACNH, AO--CO--NH, N 2 HSO, HANSO, A 2 NSO, H 2 NSO 2 , HANSO 2 , A 2 NSO 2 , H 2 NCO, HANCO, A 2 NCO, A 2 NCS, HANCS, A 2 NCS, ASONH, ASO 2 NH, ASO--ONH, AOSO 2 NH, ACO-alkyl, nitroalkyl, cyanoalkyl, A--C( ⁇ NOH) or A--C
  • R r is H or A
  • Z is O, S, NH or a single bond
  • A represents a C 1-6 alkyl group
  • -alkyl represents a C 1-6 alkylene
  • Ac represents a C 1-8 alkanoyl or C 7-11 aroyl group.
  • the above compounds have been reported to be useful in the treatment of hypertension. However, another use of the compounds was reported in such references as Br. J. Pharmacol. 89, 395-405(1986), Br. J. Pharmacol. 165, 231-239(1989), and Br. J. Pharmacol. 95, 765-770(1988): i.e., the compounds may be used as a bronchodilator in addition to a blood pressure-lowering agent, since they relax smooth muscle by enhancing the hyperpolarization of the plasma membrane of a cell.
  • the present invention primarily pertains to novel benzopyran derivatives having excellent effectiveness in the treatment of both hypertension and asthma. Further, the present invention relates to processes for preparing such compounds; and to pharmaceutical compositions containing such compounds as an active ingredient.
  • the present invention provides novel benzopyran derivatives of formula ##STR7## wherein R 1 is --CN, --NO 2 , --OCX 1 X 2 X 3 , --NH 2 , --NHSO 2 R A , ##STR8## SO 2 R C or --SO 2 NR C R D wherein X 2 , X 2 and X 3 are, each independently, F, Cl or H, except that X 1 , X 2 and X 3 may not be a hydrogen simultaneously; R A and R B are, each independently, a hydrogen atom, or a C 1-6 alkyl group or an optionally substituted phenyl group with a halogen atom, or a straight or branched C 1-3 alkyl group; and R C and R D are, each independently, a hydrogen atom or a C 1-6 alkyl group or an optionally substituted phenyl group with a halogen atom, or a straight or branched C 1-3 alkyl group;
  • R 2 is a C 1-4 straight or branched alkyl group
  • R 3 is a C 1-4 straight or branched alkyl group, ##STR9## wherein R G and R H are, each independently, a C 1-6 alkyl group or an optionally substituted phenyl group with a halogen atom, or a straight or branched C 1-3 alkyl group; A and B are, each independently, S or O; and Z is a C 1-3 straight or branched alkyl group;
  • X is N or N ⁇ O, provided, however, when X is in 2-position, ##STR10## Y is a hydrogen or halogen atom, or an amino, hydroxy, lower alkoxy or lower alkyl group.
  • Preferred benzopyran derivatives of the present invention are the compounds of formula(I) wherein:
  • R 1 is --CN or --NO 2 ;
  • R 2 is a methyl group
  • R 3 is a methyl group, ##STR11## X is N ⁇ O, provided, however, when X is in 2-position, R 3 is not a methyl group;
  • Y is H.
  • More preferred benzopyran derivatives of the present invention are the compounds of formula(l) wherein:
  • R 1 is --CN or --NO 2 ;
  • R 2 is a methyl group
  • R 3 is a methyl group, ##STR12## X is N ⁇ O, provided, however, when X is in 2-position, R 3 is not a methyl group;
  • Y is H.
  • novel benzopyran compounds of formula(I) may be present in the form of a racemic mixture of optically active isomers of formulae(I') and (I") when R 2 and R 3 are different. Each of the isomers may be obtained separately which are also within the scope of the invention. Accordingly, the compounds of formula(I) include both isomers of formulae(I') and (I") as well as the racemic mixture thereof: ##STR13## wherein R 1 , R 2 , R 3 , X and Y have the same meanings as defined above.
  • the present invention also provides processes for preparing the compounds of formula(i).
  • benzopyran derivatives having the formula(1) according to the present invention may be prepared by a known method, for example, taught in EP 298452 A2, of which details are not disclosed herein.
  • the compounds of the present invention may also be prepared by employing a novel process shown in the following Reaction Scheme(1): ##STR14## wherein R 1 , R 2 , R 3 and Y have the same meanings defined above; and R 4 is a C 1-4 alkyl group.
  • Step(a) may be conducted by reacting a ketone derivative of formula(II) with anhydrous trifluorosulfonic acid and a tertiary amine in a solvent such as dichloromethane and chloroform at a temperature ranging from 0° C. to a room temperature; or, alternatively, converting the ketone derivative of formula(II) to an enolate by using a base such as lithium diisopropyl amine, lithium dihexamethylsilazamide, etc.
  • a base such as lithium diisopropyl amine, lithium dihexamethylsilazamide, etc.
  • Tf 2 NPh N-phenyltrifluoromethane sulfonimide
  • Tf 2 NPh N-phenyltrifluoromethane sulfonimide
  • a solvent such as tetrahydrofuran(THF), ethers, THF-hexamethylphosphoric triamide (HMPA) or THF-tetramethyl ethylene diamine(TMEDA) at a temperature ranging from -78° C. to 0° C. under argon or nitrogen atomspheric environment to provide a vinyl triflate of formula(III).
  • Step(b) may be conducted by reacting the vinyl triflate of formula(III) with a trialkyltin derivative of formula(IV) in the presence of a catalyst to provide a benzopyran derivative of formula(I-a).
  • Step(b) may be carried out in a solvent such as THF, N-methyl pyrrolidone(NMP) and dimethylformamide(DMF) in the presence of a catalytic mixture of a first component selected from the group consisting of tetrakis triphenylphosphine palladium, bisbenzylidine acetone palladium and dipalladium trisdibenzylidine acetone chloroform and a second component selected from the group consisting of triphenylphosphine, tri-2-furanylphosphine and triphenyl arsenic and using a chloride compound such as lithium chloride and sodium chloride at a temperature ranging from a room temperature to 70° C.; or alternatively, in a solvent such as THF in
  • Step(c) may be conducted by oxidizing the compound of formula(I-a) in the presence of an oxidizing agent to provide a benzopyran derivative of formula(I-b) of the present invention.
  • the oxidizing agent includes m-chloroperbenzoic acid, hydrogen peroxide, dimethyldioxiran, oxon, etc; and, dichloromethane, chloroform, acetone or dioxane-water can be used as a reaction solvent.
  • the reaction temperature may range from 0° C. to a room temperature.
  • a compound of formula(I-c) may be further reacted to produce a compound of formula(I-d) or (I-e) by a process shown in the following Reaction Scheme(2): ##STR15## wherein R 1 , R 2 , A, B, X, Y and Z have the same meanings as defined above; and R' is a C 2-6 alkyl group or an optionally substituted phenyl group.
  • Step(d) may be conducted by transacetallization of a compound of formula(I-c) with an excess amount of an alcohol of formula(V) or a diol or mercaptoalcohol of formula(VI) to provide a compound of formula(I-d) or (I-e), respectively.
  • An acid catalyst may be usd in a catalytic amount; and examples of such acid catalyst include a conventional Lewis acid such as boron trifluoride, and p-toluene sulfonic acid.
  • a halogen substituted solvent such as dichloromethane and chloroform may be used; and when p-toluene sulfonic acid is employed as the catalyst, a solvent such as benzene and toluene may be used.
  • the reaction temperature may range from a room temperature to the boiling point of the solvent employed.
  • each of the optically active compounds of formulae(I') and (I") of the present invention may be separately obtained, for example, by a process shown in the following Reaction Scheme(3): ##STR16## wherein R 1 , R 2 , R 3 , X and Y have the same meanings as defined above.
  • Step(e) may be conducted by reducing a ketone derivative of formula(II) by using a reducing agent to provide an alcoholic derivative of formula(VII); the alcoholic derivative is split into two diastereomeric alcohol mixtures of formulae(VII') and (VII") by employing chromatography.
  • the reducing agent are sodium borohydride, zinc borohydride, diisobutyl aluminum hydride(DIBAL), L-selectride, borane, etc; and, as a solvent, ethers, tetrahydrofuran, dimethoxyethane(DME), toluene, etc. may be used.
  • the reaction temperature may range from -78° C. to a room temperature.
  • Step(f) may be conducted by reacting each of the diastereomeric alcohol mixtures of formulae(VII') and (VII") with a chiral carbon-containing organic acid such as (-)- ⁇ -methoxy- ⁇ -phenylacetic acid in the presence of a condensation promoting agent and a catalyst so as to produce condenstion products; and resolving said condensation products into four separate diastereomers by employing a conventional column chromatography or a recrystallization method.
  • the condensation promoting agent may include N, N-disubstituted carbodiimides such as N,N-dicyclohexylcarboimide and imidazols such as N,N-carbonyldiimidazole.
  • the catalyst include 4-dimethylaminopyridin; and, a solvent such as ethyl acetate and dichloromethane may be used.
  • Step(g) may be conducted by hydrolyzing each of the four diastereomers to obtain the compounds of formulae(VII'-a), (VII'-b), (VII"-a) and (VII"-b), which are optically active, respectively.
  • a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.; and a solvent such as alcohols(for example, methanol), alcohol-water, THF-water, dioxane-water mixtures may be used in the hydrolysis procedure.
  • Step(h) may be conducted by oxidizing each of the isomers obtained in Step(g) to obtain each of the ketone derivatives of formulae(II') and (II") which are optically active.
  • an oxidizing agent such as chromic trioxidepyridine, pyridinium chlorochromate(PCC), pyridinium dichromate(PDC) may be employed; and a solvent such as dichloromethane may be used.
  • the oxidization may be conducted by employing a conventional method, for example, using acyl chloride, dimethylsulfoxide(DMSO) and a base.
  • Step(i) may be conducted by the same procedure as shown in the above Reaction Schemed); and the reaction conditions in this step are the same as defined in Steps(a), (b) and (c) of Reaction Schemed).
  • the compounds of formula(I) of the present invention have excellent effectiveness in the treatment of hypertension by lowering blood pressure with a relaxation activity on vascular smooth muscle; and, further, in the treatment of asthma by relaxing respiratory smooth muscle.
  • the present invention also provides pharmaceutical compositions containing the compounds of formula(I) of the present invention as an active ingredient.
  • the present invention provides pharmaceutical compositions containing an effective amount of the compounds of formula(l) and conventional and pharmaceutically acceptable carriers.
  • composition of the present invention can be formulated for oral or other foms of administration, preferably oral administration.
  • the formulated composition are preferably in the form of a unit dose.
  • suitable unit dose forms may tablet, capsule and powder.
  • the effective unit-dose may comprise 0.1 to 10 mg, preferably 1 to 5 mg of the compound of the present invention.
  • composition of the present invention may be formulated with conventional additives, for example a filler, dispersant, binder, lubricant, favoring agent, etc.
  • a filler for example a filler, dispersant, binder, lubricant, favoring agent, etc.
  • the formulation of the composition can be conducted by using a known method in the art.
  • Example 11 Similarly to the procedures described in Example 10 above, the desired compound was prepared using the end product of Example 11.
  • Example 13 Similarly to the procedures described in Example 10 above, the desired compound was prepared using the end product of Example 13.
  • Example 15 Similarly to the procedures described in Example 10 above, the desired compound was prepared using the end product of Example 15.
  • the resultant mixture was diluted with 100 ml of ethyl acetate and washed with 30 ml of saturated sodium chloride solution.
  • the organic layer was dried over anhydrous magnesium sulfate, evaporated to remove the solvent and purified by silica gel column chromatography using a mixture of hexane and ethyl acetate (4:1) as an eluent to obtain 4.29 g (9.73 mmole, yield 75%) of the title compound.
  • step 1 of Example 18 the title compound was prepared using the compound obtained in step 1 of Example 11 above.
  • the reaction mixture was cooled to room temperature after completion of the reaction, diluted with 20 ml of ethyl acetate, washed with 10 mg of a saturated NaHCO 3 solution and then 10 ml of saturated sodium chloride solution, dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure.
  • the residue obtained was purified by silica gel column chromatography using a mixture of hexane and ethyl acetate (1:1) as an eluent to obtain 145 mg (0.41 mmole, yield 85%) of the desired compound as a white solid.
  • the reaction mixture was cooled to room temperature after completion of the reaction, diluted with 10 ml of ethyl acetate, washed with 10 ml of a saturated NaHCO 3 solution and then 10 ml of saturated sodium chloride solution, dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure.
  • the residue so obtained was purified by silica gel column chromatography using a mixture of hexane and ethyl acetate (1:1) as an eluent to obtain 130 mg (0.42 mmole, yield 87%) of the desired compound as a white solid.
  • Example 21 and 22 above the desired compound was prepared using the compound obtained in Example 17 above.
  • Example 21 and 22 above the desired compound was prepared using the compound obtained in Example 19 above.
  • Example 21 and 22 above the desired compound was prepared using the compound obtained in Example 18 above.
  • Example 25 Similarly to the procedures described in Example 25 above, the desired compound was prepared using the compound obtained in Example 20 above.
  • Example 25 Similarly to the procedures described in Example 25 above, the desired compound was prepared using the compound obtained in Example 17 above.
  • Example 25 Similarly to the procedures described in Example 25 above, the desired compound was prepared using the compound obtained in Example 19 above.
  • Example 21 and 22 above the desired compound was prepared using the compound obtained in Example 10 above.
  • Example 21 and 22 above the desired compound was prepared using the compound obtained in Example 9 above.
  • Example 21 and 22 above the desired compound was prepared using the compound obtained in Example 12 above.
  • Example 21 and 22 above the desired compound was prepared using the compound obtained in Example 11 above.
  • Example 25 Similarly to the procedures described in Example 25 above, the desired compound was prepared using the compound obtained in Example 10 above.
  • Example 9 the desired compound was prepared using the compound obtained in Example 9 above.
  • Example 25 Similarly to the procedures described in Example 25 above, the desired compound was prepared using the compound obtained in Example 12 above.
  • Example 25 Similarly to the procedures described in Example 25 above, the desired compound was prepared using the compound obtained in Example 11 above.
  • the relaxation activity on respiratory smooth muscle was determined as follows: Guinea pig trachea muscle was made to be contracted with histamine; and, then, the test compounds of the present invention were administered thereto; and the concentration of the test compounds which was required in relaxing 50% level of the contraction was designated as EC 50 . These EC 50 values for the test compounds are also shown in Table 1.
  • the compounds prepared in Examples 1 and 11 were orally administered to sets of rats, which had a body weight of 100-120 g and were about four week-old. Six pairs (each pair consisting of a male and a female) of the rats were used in the test. The number of the rats which died over a period of 48 hours was reported. The results of the test are shown in Table 2.
  • the compounds of the present invention are judged to be safe for use, especially at the amount to be administered.

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  • Organic Chemistry (AREA)
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  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
US07/887,189 1991-05-22 1992-05-21 Spiro-benzopyran derivatives and useful for treating asthma and hypertension Expired - Fee Related US5300511A (en)

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KR910008244 1991-05-22
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KR910008915 1991-05-30
KR91-24353 1991-12-26
KR1019910024353A KR950009863B1 (ko) 1991-05-22 1991-12-26 벤조피란 유도체와 그의 제조방법

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US5889045A (en) * 1996-11-26 1999-03-30 Adir Et Compagnie Benzopyran compounds
US5905156A (en) * 1995-05-24 1999-05-18 Novartis Ag Benzopyrans and pharmaceutical compositions containing them
US6455554B1 (en) 1999-06-07 2002-09-24 Targacept, Inc. Oxopyridinyl pharmaceutical compositions and methods for use
US20080044747A1 (en) * 2005-08-30 2008-02-21 Xerox Corporation Solvent-less process for producing transient documents

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US5719155A (en) 1993-11-10 1998-02-17 Japan Tobacco Inc. Chroman derivative and pharmaceutical use thereof
WO2005037830A1 (fr) * 2003-10-10 2005-04-28 Wyeth Composes de piperidinylchromen-6-yl-sulfonamide utilises comme ligand de la 5-hydroxytryptamine-6
KR101975927B1 (ko) 2012-12-13 2019-05-08 삼성전자주식회사 설치류 기도내 삽관용 고정 장치

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DE3922392A1 (de) * 1989-07-07 1991-01-17 Merck Patent Gmbh Chromanderivate
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US4578410A (en) * 1983-09-05 1986-03-25 Sumitomo Chemical Company, Limited Piperidine derivatives, their production and stabilized polymer compositions containing same

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5397783A (en) * 1992-04-01 1995-03-14 Adir Et Compagnie 3-aminochroman spiro compounds
US5905156A (en) * 1995-05-24 1999-05-18 Novartis Ag Benzopyrans and pharmaceutical compositions containing them
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KR950009863B1 (ko) 1995-08-29
DK0514942T3 (da) 1997-03-24
KR920021537A (ko) 1992-12-18
US5493029A (en) 1996-02-20
GR3022761T3 (en) 1997-06-30
JP3153339B2 (ja) 2001-04-09
DE69217717T2 (de) 1997-09-11
ES2099180T3 (es) 1997-05-16
EP0514942B1 (fr) 1997-03-05
DE69217717D1 (de) 1997-04-10
ATE149494T1 (de) 1997-03-15
EP0514942A1 (fr) 1992-11-25
JPH05194496A (ja) 1993-08-03

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